Background: Focal adhesion kinase (FAK) is consistently hyperactivated in pancreatic ductal adenocarcinoma (PDAC), and FAK signaling is a key driver in forming its fibrotic and proinflammatory tumor microenvironment. Inhibition of FAK signaling leads to significant reduction of pancreatic tumor growth in animal models. Indeed, tumors treated with FAK inhibitors displayed markedly reduced tumor fibrosis and decreased immunosuppressive myeloid cells. Furthermore, our preclinical work has demonstrated that FAK- and PD-1 inhibitors elicit significant tumor regression, and the maximal response was achieved by combining FAK- and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation (Jiang H et al, Nature Medicine 2016). Defactinib is an orally available, potent ATP-competitive, FAK inhibitor with a recommended phase II dose (RP2D) of 400 mg twice daily. Methods: Eligible patients will be treated according to the dose escalation schema. A 3+3 design is used until the first occurrence of dose-limiting toxicity, and then switches to a continuous assessment design. The study has an expansion portion (group A and B) at the RP2D. Group A includes metastatic PDAC patients who are stable at least 4 months on front-line nab-paclitaxel/gemcitabine, and group B includes metastatic PDAC patients progressed on ≥ 1 chemotherapy line. Key eligibility criteria include patients with advanced solid tumors (dose escalation portion) or advanced PDAC (expansion cohort); age ≥18 years; ECOG score ≤1; normal organ function; and no history autoimmunity. The primary endpoint is to determine the RP2D. Secondary endpoints include objective response rate, progression-free survival and overall survival. The exploratory endpoints include developing a molecular and immune signature for treatment response. This trial is actively enrolling and funded by Precision Medicine Research Associate and Barnes Jewish Foundation. Clinical trial information: NCT02546531